Brigatinib

Brigatinib is a tyrosine kinase inhibitor with in vitro activity at clinically achievable concentrations against multiple kinases, including ALK, ROS1, insulin-like growth factor-1 receptor (IGF-1R), FLT-3, and EGFR deletion and point mutations.

Brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of downstream signaling proteins STAT3, AKT, ERK1/2, and S6 in in vitro and in vivo assays. It exhibited in vivo antitumor activity against 4 mutant forms of EML4-ALK, including G1202R and L1196M mutants identified in NSCLC tumors in patients who have progressed on crizotinib.

Brigatinib is indicated for ALK-positive metastatic NSCLC in patients who have progressed on or are intolerant to crizotinib.

• Anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) - in patients who have progressed on or are intolerant to crizotinib

Adults (ALK-positive metastatic NSCLC):
First 7 days: 90 mg PO qDay (with or without food).
If 90 mg/day is tolerated: Increase dose to 180 mg PO qDay.
Continue until disease progression or unacceptable toxicity.

Hepatic impairment:
Mild or moderate (Child-Pugh A or B): No dose adjustment required.
Severe (Child-Pugh C): Reduce once daily dose by ~40% (e.g., 180 mg to 120 mg, 120 mg to 90 mg, or 90 mg to 60 mg).

Renal impairment:
Mild or moderate (CrCl 30-89 mL/min): No dose adjustment required.
Severe (CrCl 15-29 mL/min): Reduce dose by ~50% (e.g., 180 mg to 90 mg, or 90 mg to 60 mg).

>10%: Increased AST (38%), Hyperglycemia (38%), Increased ALT (34%), Nausea (33%), Fatigue (29%), Headache (28%), Increased CPK (27%), Increased amylase (27%), Dyspnea (27%), Vomiting (24%), Anemia (23%), Decreased appetite (22%), Prolonged aPTT (22%), Increased lipase (21%), Diarrhea (19%), Constipation (19%), Lymphopenia (19%), Cough (18%), Abdominal pain (17%), Increased alkaline phosphatase (15%), Decreased phosphorous (15%), Rash (15%), Pyrexia (14%), Arthralgia (14%), Peripheral neuropathy (13%), Muscle spasms (12%), Hypertension (11%), Pain in extremity (11%), Insomnia (11%).

1-10%: Back pain (10%), Myalgia (9.2%), Visual disturbances (7.3%), Pneumonia (4.6%), Interstitial lung disease/pneumonitis (3.7%).

<1%: Hypoxia (0.9%).

• Interstitial lung disease (ILD)/pneumonitis: Risk exists; discontinue for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1/2 ILD.
• Hypertension (HTN): Discontinue for Grade 4 HTN or recurrence of Grade 3 HTN.
• Bradycardia: Discontinue for life-threatening bradycardia; caution with antihypertensives causing bradycardia.
• Visual disturbances: Blurred vision, diplopia, reduced visual acuity; discontinue for Grade 4.
• CPK and pancreatic enzyme elevation: Withhold treatment for Grade 3 or 4 elevation.
• Hyperglycemia: Withhold treatment for inadequate glycemic control.
• Contraception: Females of reproductive potential should use effective non-hormonal contraception during treatment and for at least 4 months after the final dose; males should use effective contraception during treatment and for at least 3 months after the last dose.
• Do not use during pregnancy and lactation; not for use in children.

• Hypersensitivity to brigatinib or any of its components

• Strong CYP3A inhibitors (boceprevir, cobicistat, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, itraconazole, ketoconazole, posaconazole, voriconazole, conivaptan): Increase brigatinib plasma concentrations and adverse reactions.
• Grapefruit or grapefruit juice: May increase brigatinib levels; avoid.
• Strong CYP3A inducers (rifampin, carbamazepine, phenytoin, St. John's Wort): Decrease brigatinib plasma concentrations and efficacy.
• CYP3A substrates (e.g., hormonal contraceptives): Decreased concentrations and loss of efficacy.